Blister package for inhalable medicament

ABSTRACT

There is provided a blister form medicament pack comprising (a) a base sheet in which blisters are formed to define pockets therein for the containment of inhalable medicament; and (b) a lid sheet which is sealable to the base sheet except in the region of the blisters and mechanically peelable from the base sheet to enable release of said inhalable medicament. The base sheet and/or said lid sheet have a laminate structure comprising (a) a first layer of aluminum foil; and (b) a second layer of polymeric material of thickness from 10 to 60 micron, said polymeric material having a water vapor permeability of less than 0.6 g/(100 inches 2 ) (24 hours) (mil) at 25° C.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is filed pursuant to 35 U.S.C. § 371 as a United StatesNational Phase Application of International Application No.PCT/EP2003/012159 filed Oct. 30, 2003, which claims priority from GB0225621.2 filed Nov. 2, 2002.

TECHNICAL FIELD

The present invention relates to a medicament carrier in peelableblister pack form suitable for containing medicament for inhaleddelivery to the lung.

BACKGROUND OF THE INVENTION

The use of medicament dispensers in the delivery of medicaments to thelung is well known. Such dispensers generally comprise a body or housingwithin which a medicament carrier is located. Known inhalation devicesinclude those in which the medicament carrier is in blister pack form(e.g. an elongate blister strip) containing a number of discrete dosesof powdered medicament. In use, the blister pack is typically housedwithin the dispenser in such a way that the blisters may be transportedthrough the dispenser in indexed fashion to enable accessing of thediscrete doses of medicament carried thereby. Such devices usuallycontain a mechanism of individually accessing the doses contained withinthe blisters. Known access mechanisms typically comprise either blisterpiercing means or means to peel a lid sheet away from a base sheet ofthe blister pack. The powdered medicament can then be accessed andinhaled.

It is desirable that elongate blister strip form medicament carriers forcontaining medicament in dry powder form have suitable moisture transferproperties. Whilst to an extent, the optimal character of suchproperties is dependent on the nature of the particular medicamentformulation to be carried within the blister it is generally beneficialfor the material of the strip and of any seals made thereto to eitherprevent or at least to significantly slow down moisture ingress to themedicament contained within the blister to prevent the moisture-induceddegradation or agglomeration thereof. Reducing moisture permeationreduction to the cavity of the blister pack and thereby enhancing thestability of the medicament contained therein are particular targets ofinterest. Efforts therefore continue to be expended in the developmentof improved strip materials, pack forms and sealing methods.

Conventional high barrier medicament blister packs typically comprisealuminium foil sheets in both the lid sheet and base sheet componentsthereof. The aluminium sheets are selected to have sufficient thicknessto be substantially free of ‘pinhole’ imperfections thereby making themessentially impermeable to the transfer of moisture. In developmentsthereof, laminate form sheets are used for either one or both of the lidand base sheets, which laminates typically comprise a layer of aluminiumfoil and one or more polymeric layers. Such laminates are typicallyemployed when a ‘cold form’ method is employed to form the base sheetwith blister pockets. Polyvinyl chloride (PVC) is conventionally used asthe material of the polymeric layer.

The Applicants have now appreciated that such polymeric layers act asthe principal conduit for moisture ingress to the medicament containedwithin the blisters. The absolute rate of flow of moisture is dependenton various factors including prevailing environmental conditions, thepolymer material and properties of the medicament itself (e.g.hygroscopic or desiccant properties).

The Applicants have now found that moisture ingress to the interior ofthe blister may be reduced by the selection of particular,unconventional polymeric materials for use in the laminate sheets of theblister packs. The Applicants have also found that moisture ingress mayalso be reduced by the use of polymeric layers in the laminates, whichhave reduced thickness compared to conventional polymeric layers.Enhancements in the storage stability of dry powder form medicamentcontained within the blister packs may thereby be achieved.

The Applicants have further found that certain of the new polymericmaterials can act to provide an enhanced oxygen barrier. That is to say,the layer comprising the new polymeric material acts such as to reduceoxygen permeation, and thereby also reduce oxygen ingress to themedicament contained within the blister. This can be important where themedicament is susceptible to oxidative degradation,

The Applicants have also further found that certain of the new polymericmaterials can act to modify the static electricity-related properties ofthe laminates and blister pack. This can be important where the powderform medicament is susceptible to adhere to the interior of a blistercavity because of static electricity effects thereby affecting theability to release/deliver the powder from an opened blister pack.

SUMMARY OF THE INVENTION

According to one aspect of the invention there is provided a blisterform medicament pack comprising

-   (a) a base sheet in which blisters are formed to define pockets    therein for the containment of inhalable medicament;-   (b) a lid sheet which is sealable to the base sheet except in the    region of the blisters and mechanically peelable from the base sheet    to enable release of said inhalable medicament,    wherein said base sheet and/or said lid sheet have a laminate    structure comprising (a) a first layer of aluminium foil; and (b) a    second layer of polymeric material of thickness from 10 to 60    micron, said polymeric material having a water vapour permeability    of less than 0.6 g/(100 inches²) (24 hours) (mil) at 25° C.

The water vapour permeability is suitably measured by ASTM test methodno. ASTM E96-635 (E).

Suitably, the polymeric material comprises a material selected from thegroup consisting of polypropylene (e.g. in oriented or cast form;standard or metallocene); polyethylene (e.g. in high, low orintermediate density form); polyvinylidene chloride (PVDC);polychlorotrifluoroethylene (PCTFE); cyclic olefin copolymer (COC); andcyclic olefin polymer (COP).

Where the polymeric material is selected from the group consisting ofpolyethylene (in high density form), polypropylene or polyvinylidenechloride (PVDC), reduced oxygen permeation through the polymeric layer,and hence to the interior of the blister, may be achieved. Oxygenpermeation through the polymeric layer may be tested using ASTM testmethod D3985-81, in which such oxygen transmission is measured at 25° C.and 50% Relative Humidity.

The medicament carrier has a blister pack form, particularly a blisterstrip having multiple distinct blister portions provided along itslength. The blisters may have any suitable shape including those with asquare, circular or rectangular profile.

The medicament carrier suitably has multiple distinct (i.e. separate)medicament doses carried thereby, and may for example, be in the form ofa peelable blister strip, disk or other suitable blister pack form.

The medicament carrier is in the form of a peelable blister pack,particularly an elongate form peelable blister strip. The peelableblister pack comprises a base sheet in which blisters are formed todefine pockets therein for the containment of inhalable medicament and alid sheet which is hermetically sealed to the base sheet except in theregion of the blisters in such a manner that the lid sheet and the basesheet can be peeled apart to enable release of the inhalable medicamentfrom one or more pockets thereof. The term ‘inhalable medicament’ isused herein to mean medicament suitable for inhaled delivery to thelung.

The base and lid sheets are typically sealed to one another over theirwhole width except for the forward end portions where they are typicallynot sealed to each other at all. Thus, separate base and lid sheetforward end portions are presented at the end of the strip.

The lid sheet and/or base sheet of the medicament carrier herein are inthe form of a laminate, which comprises multiple layers of differentmaterials.

The base sheet and/or lid sheet herein comprises (a) a first layer ofmetal foil, particularly aluminium foil; and (b) a second layer ofpolymeric material having a water vapour permeability of less than 0.6g/(100 inches²) (24 hours) (mil) at 25° C.

The second layer comprises a polymeric material of low water vapourpermeability. The water vapour permeability is less than 0.6 g/(100inches²) (24 hours) (mil) at 25° C., but preferably less than less than0.3 g/(100 inches²) (24 hours) (mil) at 25° C. as suitably measured byASTM E96-635 (E) which defines a standard test method for measuringwater vapour permeability.

The second layer of the base sheet and/or lid sheet is generally aninner layer of the overall medicament carrier pack.

Suitably, the polymeric material is selected from the group consistingof polypropylene (in oriented or cast form; standard or metallocene);polyethylene (in high, low or intermediate density form); polyvinylidenechloride (PVDC); polychlorotrifluoroethylene (PCTFE); cyclic olefincopolymer (COC); and cyclic olefin polymer (COP). Optionally, otherlayers of material are also present.

Material sold under the trade name Aclar by Honeywell Inc, a UnitedStates corporation is a suitable polychlorotrifluoroethylene (PCTFE)polymeric material herein. Suitable cyclic olefin copolymer (COC) issold by Hoechst AG of Germany, under the trade name Topaz. A suitablecyclic olefin polymer is sold by Nippon Zeon Co. Ltd of Tokyo, Japanunder the trade name Zenor.

Suitably polypropylene polymeric material is manufactured by a processin which a one or more metallocene compounds is employed to modifyand/or control the nature of any side-chain groups thereof.

The thickness of the second layer of polymeric material is from 10 to 60micron. Preferably, the thickness of the polymeric layer is optimised toreduce moisture ingress, and particularly is from 20 to 30 micron.

Suitably, the lid sheet comprises at least the following successivelayers: (a) paper; bonded to (b) plastic film; bonded to (c) aluminiumfoil.

The aluminium foil typically coated with a layer (e.g. of heat seallacquer; film or extrusion coating) for bonding to the base sheetmaterial.

The thickness of each of the layers of the lid sheet may be selectedaccording to the desired properties but is typically of the order offrom 5 to 200 micron, particularly from 10 to 50 micron.

The plastic layer is in one aspect, suitably selected from polyester(non-oriented, monaxial, or biaxial oriented), polyamide, polypropyleneor PVC. In another aspect the plastic film is an oriented plastic film,suitably selected from oriented polyamide (OPA); oriented polyester(OPET); and oriented polypropylene (OPP). The thickness of the plasticlayer is typically from 5 to 40 μm, particularly 12 to 30 μm.

The thickness of the aluminium layer is typically from 15 to 60 μm,particularly 20 to 40 μm.

In aspects, the paper layer comprises a paper/extrusion layer, optimallylaminated to aluminium.

In one particular aspect, the lid sheet comprises at least the followingsuccessive layers: (a) paper; bonded to (b) polyester; bonded to (c)aluminium foil; that is coated with a heat seal lacquer for bonding tothe base sheet. The thickness of each layer may be selected according tothe desired properties but is typically of the order of from 5 to 200micron, particularly from 10 to 50 micron.

The bonding may in aspects be provided as an adhesive bond (e.g.solvent-based adhesive wherein the solvent is organic or water-based);solvent free adhesive bond; extrusion laminated bond; or heatcalendaring.

In another particular aspect, the base sheet comprises at least thefollowing successive layers: (a) oriented polyamide (OPA); adhesivelybonded to (b) aluminium foil; adhesively bonded to (c) a third layer ofthickness from 10 to 60 micron comprising a polymeric material. Thepolymeric material has a water vapour permeability of less than 0.6g/(100 inches²) (24 hours) (mil) at 25° C. The third layer will bondwith the lid sheet, which is generally treated with a heat seal lacquer.

The thickness of each non-polymeric layer of the base sheet may beselected according to the desired properties but is typically of theorder of from 5 to 200 micron, particularly from 40 to 60 micron. Inaccord with the invention, the thickness of the polymeric layer isselected to reduce moisture ingress, and is from 10 to 60 micron, moreparticularly from 20 to 30 micron.

Suitably, the polymeric material is selected from the group consistingof polypropylene (in oriented or cast form; standard or metallocene);polyethylene (in high, low or intermediate density form); polyvinylidenechloride (PVDC); polychlorotrifluoroethylene (PCTFE); cyclic olefincopolymer (COC); and cyclic olefin polymer (COP). Optionally, otherlayers of material are also present.

One particular base sheet comprises the following successive layers: (a)oriented polyamide (OPA); adhesively bonded to (b) aluminium foil;adhesively bonded to (c) oriented polypropylene (OPP). The thickness ofthe polymeric layer is from 10 to 60 micron, particularly from 20 to 30micron.

Another particular base sheet comprises the following successive layers:(a) oriented polyamide (OPA); adhesively bonded to (b) aluminium foil;adhesively bonded to (c) cast polypropylene. The thickness of thepolymeric layer is from 10 to 60 micron, particularly from 20 to 30micron.

A further particular base sheet comprises the following successivelayers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminiumfoil; adhesively bonded to (c) high density polyethylene (HDPE). Thethickness of the polymeric layer is from 10 to 60 micron, particularlyfrom 35 to 45 micron.

A further particular base sheet comprises the following successivelayers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminiumfoil; adhesively bonded to (c) low density polyethylene (LDPE). Thethickness of the polymeric layer is from 10 to 60 micron, particularlyfrom 20 to 30 micron.

A further particular base sheet comprises the following successivelayers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminiumfoil; adhesively bonded to (c) polyvinylidene chloride (PVDC). Thethickness of the polymeric layer is from 10 to 60 micron, particularlyfrom 20 to 30 micron. The grade of the PVDC is generally from 8 to 95gsm, particularly from 10 to 40 gsm.

A further particular base sheet comprises the following successivelayers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminiumfoil; adhesively bonded to (c) polychlorotrifluoroethylene (PCTFE). Thethickness of the polymeric layer is from 10 to 60 micron, particularlyfrom 20 to 45 micron.

A further particular base sheet comprises the following successivelayers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminiumfoil; adhesively bonded to (c) cyclic olefin copolymer (COC). Thethickness of the polymeric layer is from 10 to 60 micron, particularlyfrom 20 to 30 micron.

A further particular base sheet comprises the following successivelayers: (a) oriented polyamide (OPA); adhesively bonded to (b) aluminiumfoil; adhesively bonded to (c) cyclic olefin polymer (COP). Thethickness of the polymeric layer is from 10 to 60 micron, particularlyfrom 20 to 30 micron.

Various known techniques can be employed to join the lid and base sheetand hence to seal the blisters. Such methods include adhesive bonding,radio frequency welding, ultrasonic welding and hot bar sealing.

The base sheet herein is particularly suitable for forming by ‘coldform’ methods, which are conducted at lower temperatures thanconventional methods (e.g. at close to room temperature). Such ‘coldform’ methods are of particular utility where the medicament ormedicament formulation for containment within the blister is heatsensitive (e.g. degrades or denatures on heating).

One method for forming a medicament carrier herein comprises the stepsof (a) providing a base sheet having a first mating surface and a lidsheet a having a second mating surface, the base sheet including atleast one blister having a periphery region, the blister being adaptedto receive a medicament composition; (b) filling the blister with thepharmaceutical composition; (c) bonding the base sheet to the lid sheetto create a primary seal therebetween. The medicament carrier can be ofany shape for good airflow (e.g. to assist aerosolisation of the powdercontained therein), preferably, substantially elongated or substantiallycircular.

Suitably, the base sheet includes at least a first bonding materialdisposed on the first mating surface and the lid sheet includes at leasta second bonding material disposed on the second mating surface. In oneembodiment, one or both of the first or second bonding materialscomprises at least one polymeric material. In an additional embodiment,one or both of the first or second bonding material comprises asubstance that enables peelable separation e.g. a heat seal lacquer,plastic film or coating.

A suitable manufacturing system herein comprises (a) a base transporterfor transporting a base sheet to a filling station, the base sheetincluding at least one blister pocket adapted to receive an inhalablemedicament composition, the base sheet further including a first bondingmaterial; (b) a filling apparatus for filling the blister with theinhalable medicament composition; (c) a lid transporter for transportinga lid sheet proximate to the filled base sheet, the lid sheet includinga second bonding material; (d) a bonding mechanism for bonding the firstand second bonding materials to create a primary seal therebetween.

In use, the medicament carrier is suitably receivable by a medicamentdispenser that comprises a housing for receipt of the medicamentcarrier. In one aspect, the medicament dispenser has unitary form andthe housing is integral therewith. In another aspect, the medicamentdispenser is configured to receive a refill cassette and the housingforms part of that refill cassette.

Suitably, the interior of the housing is shaped, or alternativelyprovided with specific guiding features, to guide the medicament carrierappropriately into the housing. In particular, the guiding should ensurethat the medicament carrier is suitably located to interact withinternal mechanisms (e.g. indexing and opening mechanisms) of thehousing.

Suitably, the dispenser has an internal mechanism for dispensing thedistinct inhalable medicament doses carried by the medicament carrierfor administration to the patient (e.g. by inhalation). Suitably, themechanism comprises,

-   a) receiving means for receiving the medicament carrier;-   b) release means for releasing a distinct medicament dose from the    medicament carrier on receipt thereof by said receiving means;-   c) an outlet, positioned to be in communication with the medicament    dose releasable by said release means;-   d) indexing means for individually indexing the distinct medicament    doses of the medicament carrier; and-   The mechanism comprises receiving means (e.g. a receiving station)    for receiving the medicament carrier.

The mechanism further comprises release means for releasing a distinctmedicament dose from the medicament carrier on its receipt by thereceiving station. The release means typically comprises means formechanically peeling apart the blister strip.

An outlet is positioned to be in communication with the distinctmedicament doses releasable by said release means. The outlet may haveany suitable form. In one aspect, it has the form of a mouthpiece and inanother, it has the form of a nozzle for insertion into the nasal cavityof a patient.

The outlet is preferably a single outlet, which communicates with thedistinct medicament dose releasable by said release means via a commonair channelling means (e.g. formed as an air-pipe or common manifold).The patient may therefore breathe in through a single outlet, and thatbreath be transferred through the common channelling means to thereleased medicament dose, thereby enabling its inhalation.

The mechanism also comprises indexing means for individually indexingthe distinct medicament doses of the medicament carrier. Said indexingtypically happens in sequential fashion, for example accessing doseportions sequentially arranged along the length of the elongate carrier.

Optionally, the medicament dispenser also includes counting means forcounting each time a distinct medicament dose of the medicament carrieris indexed by said indexing means.

In one aspect, counting means is arranged to count each time a distinctmedicament dose of the medicament carrier is indexed by said indexingmeans. Suitably, the indexing means and counting means engage directlyor indirectly (e.g. via a coupling) with each other to enable countingof each indexation.

Suitably, the counting means is provided with (or communicates with) adisplay for displaying to the patient the number of distinct doses leftto be taken or the number of doses taken.

In one preferred aspect, the medicament dispenser takes the form of adispenser for use with a medicament carrier having multiple distinctpockets for containing inhalable medicament doses, wherein said pocketsare spaced along the length of and defined between two peelable sheetssecured to each other, said dispenser having an internal mechanism fordispensing the medicament doses contained within said medicamentcarrier, said mechanism comprising,

-   a) an opening station for receiving a pocket of the medicament    carrier;-   b) peeling means positioned to engage a base sheet and a lid sheet    of a pocket which has been received in said opening station for    peeling apart such a base sheet and lid sheet, to open such a    pocket, said peeling means including lid driving means for pulling    apart a lid sheet and a base sheet of a pocket that has been    received at said opening station;-   c) an outlet, positioned to be in communication with an opened    pocket through which a user can access a medicament dose from such    an opened pocket;-   d) indexing means for individually indexing the distinct pockets of    the medicament carrier.

Suitably, the indexing means comprises a rotatable index wheel havingrecesses therein, said index wheel being engageable with a medicamentcarrier in use with said medicament dispenser such that said recesseseach receive a respective pocket of the base sheet of a blister strip inuse with said medicament dispenser.

According to another aspect of the present invention there is provided amedicament dispenser comprising (e.g. loaded with) at least onemedicament carrier wherein.

BRIEF DESCRIPTION OF THE DRAWINGS

The invention will now be described with reference to the accompanyingdrawings in which:

FIG. 1 shows a perspective view of the form of a medicament carrier of aform suitable for use in accord with the present invention;

FIG. 2 shows a top view of the form of a medicament carrier of a formsuitable for use in accord with the present invention;

FIG. 3 shows a top view of the form of another medicament carrier of aform suitable for use in accord with the present invention; and

FIG. 4 shows a cross-sectional side view of the form of a laminate formmedicament carrier in accord with the present invention.

DETAILED DESCRIPTION OF THE DRAWINGS

FIG. 1 shows a medicament carrier 100 that may be constructed to have adetailed form in accord with the present invention. The medicamentcarrier comprises a flexible strip 101 defining a plurality of pockets103, 105, 107 each of which would contain a portion of a dose ofmedicament which can be inhaled, in the form of powder.

The strip comprises a base sheet 109 in which blisters are formed todefine the pockets 103, 105, 107 and a lid sheet 111 which ishermetically sealed to the base sheet except in the region of theblisters in such a manner that the lid sheet 111 and the base sheet 109can be peeled apart. The sheets 109, 111 are sealed to one another overtheir whole width except for the leading end portions 113, 115 wherethey are preferably not sealed to one another at all. The lid 111 andbase 109 sheets are formed of a laminate and are preferably adhered toone another by heat sealing.

The strip 101 is shown as having elongate pockets 103, 105, and 107 thatrun transversely with respect to the length of the strip 101. This isconvenient in that it enables a large number of pockets 103, 105, 107 tobe provided in a given strip 101 length. The strip 101 may, for example,be provided with sixty or one hundred pockets but it will be understoodthat the strip 101 may have any suitable number of pockets.

Referring now to FIG. 2, there is shown a medicament carrier in the formof a laminate assembly or blister strip 200 viewed from underneath. Theblister strip has a substantially elongated shape and includes aplurality of blisters 203, 205, 207 formed in the base 209 thereofadapted to receive a pharmaceutical composition 14, preferably in theform of a dry powder. Each blister 203, 205, 207 has a length I₁ that ispreferably from 1.5 to 15.0 mm, more preferably, from 1.5 to 8.0 mm, andin an actual embodiment is equal to 7.5 mm, measured along its longeraxis, and a width I₂ that is preferably from 1.5 to 10.0 mm, morepreferably, from 1.5 to 8.0 mm, and in an actual embodiment is equal to4.0 mm, measured along its shorter axis.

In the illustrated example of FIG. 2, the blister strip 200 has a widthof 12.5 mm. The thickness of the base 209 is in the range of 75 to 200micron. The thickness of the lid is in the range 40 to 100 micron. Thecombined thickness of the base 209 and lid (not visible) isapproximately 115 to 300 micron. The blisters 203, 205, 207 aretypically at 7.5 mm spacings along the blister strip 200. Each blister203, 205, 207 contains an effective dosage of powder, preferably lessthan 30 mg of powder, more preferably, between 5-25 mg of powder, andmost preferably, approximately 12.5 mg of powder. The powder is aninhalable medicament composition comprising at least one medicamentactive.

Suitable materials are employed to construct the base 209 and lid (notvisible). In accord with the invention, the base 209 and/or lid compriselaminate structures having at least one bonding material on at least onemating surface of either the base 209 or lid. The bonding material(s)preferably comprise at least one polymeric material and a heat seatlacquer (e.g. a vinylic heat seal lacquer).

Referring now to FIG. 4, the lid of the blister pack 400 has amulti-layer structure and comprises the following successive layers:paper 425 adhesively bonded to polyester 427 adhesively bonded toaluminium foil 429 that is coated with a heat seal lacquer 430. The basealso has a multi-layer structure and comprises at least the followingsuccessive layers: oriented polyamide (OPA) 420 adhesively bonded toaluminium foil 422 adhesively bonded to a third polymer layer 424. Theblister pack 400 is filled with inhalable medicament 414 in dry powderedform.

It will be appreciated that in variations of the blister pack of FIG. 4different polymers may be used for the third polymer layer of the basesheet provided that the requirement is satisfied for the polymer to havea water vapour permeability of less than 0.6 g/(100 inches²) (24 hours)(mil) at 25° C. measured by ASTM E96-635 (E).

In one particular variation, the base sheet of the blister pack of FIG.4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 45 micron thickness aluminiumfoil 422; adhesively bonded to 30 micron thickness polyvinylidenechloride (PVDC) 424 having a water vapour permeability of less than 0.6g/(100 inches²) (24 hours) (mil) at 25° C. measured by ASTM E96-635 (E).

In another particular variation, the base sheet of the blister pack ofFIG. 4 has the following structure: 25 micron-layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminiumfoil 422; adhesively bonded to 20 micron thickness orientedpolypropylene 424 having a water vapour permeability of less than 0.6g/(100 inches²) (24 hours) (mil) at 25° C. measured by ASTM E96-635 (E).

In another particular variation, the base sheet of the blister pack ofFIG. 4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminiumfoil 422; adhesively bonded to 25 micron thickness cast polypropylene424 having a water vapour permeability of less than 0.6 g/(100 inches²)(24 hours) (mil) at 25° C. measured by ASTM E96-635 (E).

In another particular variation, the base sheet of the blister pack ofFIG. 4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminiumfoil 422; adhesively bonded to 20 micron thickness orientedpolypropylene 424 having a water vapour permeability of less than 0.6g/(100 inches²) (24 hours) (mil) at 25° C. measured by ASTM E96-635 (E).

In another particular variation, the base sheet of the blister pack ofFIG. 4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminiumfoil 422; adhesively bonded to 25 micron thickness cast polypropylene424 having a water vapour permeability of less than 0.6 g/(100 inches²)(24 hours) (mil) at 25° C. measured by ASTM E96-635 (E).

In another particular variation, the base sheet of the blister pack ofFIG. 4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminiumfoil 422; adhesively bonded to 25 micron thickness polypropylene 424,wherein the polypropylene is manufactured by a process in which one ormore metallocene compounds are employed to control side-chaincharacteristics thereof, having a water vapour permeability of less than0.6 g/(100 inches²) (24 hours) (mil) at 25° C. measured by ASTM E96-635(E).

In another particular variation, the base sheet of the blister pack ofFIG. 4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminiumfoil 422; adhesively bonded to 40 micron thickness low densitypolyethylene (LDPE) 424 having a water vapour permeability of less than0.6 g/(100 inches²) (24 hours) (mil) at 25° C. measured by ASTM E96-635(E).

In another particular variation, the base sheet of the blister pack ofFIG. 4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminiumfoil 422; adhesively bonded to 40 micron thickness high densitypolyethylene (HDPE) 424 having a water vapour permeability of less than0.6 g/(100 inches²) (24 hours) (mil) at 25° C. measured by ASTM E96-635(E).

In another particular variation, the base sheet of the blister pack ofFIG. 4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminiumfoil 422; adhesively bonded to 20 micron thicknesspolychlorotrifluoroethylene (PCTFE) 424 having a water vapourpermeability of less than 0.6 g/(100 inches²) (24 hours) (mil) at 25° C.measured by ASTM E96-635 (E). In a particular embodiment, the PCTFE ispolymeric material sold under the trade name Aclar by Honeywell Inc, aUnited States corporation.

In another particular variation, the base sheet of the blister pack ofFIG. 4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminiumfoil 422; adhesively bonded to 25 micron thickness cyclic olefincopolymer (COC) 424 having a water vapour permeability of less than 0.6g/(100 inches²) (24 hours) (mil) at 25° C. measured by ASTM E96-635 (E).In a particular embodiment, the cyclic olefin copolymer (COC) is amaterial sold by Hoechst AG of Germany, under the trade name Topaz.

In another particular variation, the base sheet of the blister pack ofFIG. 4 has the following structure: 25 micron layer thickness orientedpolyamide (OPA) 420; adhesively bonded to 60 micron thickness aluminiumfoil 422; adhesively bonded to 25 micron thickness cyclic olefin polymer(COP) 424 having a water vapour permeability of less than 0.6 g/(100inches²) (24 hours) (mil) at 25° C. measured by ASTM E96-635 (E).

As will be appreciated by one having ordinary skill in the art, variousconventional adhesives can be employed to bond the laminate layerswithin the scope of the invention. Such adhesives include, but are notlimited to, cyanoacrylates, acrylics and polyurethanes.

During a typical blister strip manufacturing process, each blister 412is filled with a pharmaceutical composition 414 and subsequently sealed.The sealing temperature and other parameters of the sealing method maybe varied including tooling, dwell time, sealing pressure and speed ofsealing. The heat-sealing step bonds the mating layers (e.g., PVC 424and heat seal lacquer 430) of the base and lid to seal each blister 412and, hence forms a secure container for the pharmaceutical composition414 contained therein. Ideally, the bonding creates a hermetic seal thatis formed. As will be appreciated, hermetically sealing each blister 412to eliminate the possibility of contamination from the externalenvironment can be an important aspect of the manufacturing process.

Various bonding schemes and patterns have been employed to bond and sealblister strips. Illustrative are the bonding schemes and patterns shownin FIGS. 2 and 3.

Referring now to FIG. 2, there is shown a bonding scheme that employssubstantially uniformly distributed heat across at least one surface ofthe blister strip 200 to create discrete bond areas of the mating base209 and lid surfaces. Although various bond patterns can be formed bythis bonding scheme (e.g., zig-zag, dot, checkered, etc.), a checkeredgrid 216 pattern is employed in this example.

As illustrated in FIG. 2, the grid 216 provides a restricted, tortuouspath (designated generally by Arrow M) for the ingress of contaminantsand/or moisture into the blisters 203, 205, 207.

Referring now to FIG. 3, there is shown a further bonding scheme thatemploys substantially uniformly distributed heat across at least onesurface of the blister strip 300 to create discrete bond areas of themating base 309 and lid surfaces. A knurled form bond pattern 316 isemployed in this example. The knurling 316 provides a restricted,tortuous path (designated generally by Arrow M) for the ingress ofcontaminants and/or moisture into the blisters 303, 305, 307.

The medicament pack and related medicament dispenser device of theinvention is suitable for dispensing medicament products particularlyfor the treatment of respiratory disorders such as asthma and chronicobstructive pulmonary disease (COPD), bronchitis and chest infections.

Appropriate medicaments may thus be selected from, for example,analgesics, e.g., codeine, dihydromorphine, ergotamine, fentanyl ormorphine; anginal preparations, e.g., diltiazem; antiallergics, e.g.,cromoglycate (e.g. as the sodium salt), ketotifen or nedocromil (e.g. asthe sodium salt); antiinfectives e.g., cephalosporins, penicillins,streptomycin, sulphonamides, tetracyclines and pentamidine;antihistamines, e.g., methapyrilene; anti-inflammatories, e.g.,beclomethasone (e.g. as the dipropionate ester), fluticasone (e.g. asthe propionate ester), flunisolide, budesonide, rofleponide, mometasonee.g. as the furoate ester), ciclesonide, triamcinolone (e.g. as theacetonide) or6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3-yl)ester; antitussives, e.g.,noscapine; bronchodilators, e.g., albuterol (e.g. as free base orsulphate), salmeterol (e.g. as xinafoate), ephedrine, adrenaline,fenoterol (e.g. as hydrobromide), formoterol (e.g. as fumarate),isoprenaline, metaproterenol, phenylephrine, phenylpropanolamine,pirbuterol (e.g. as acetate), reproterol (e.g. as hydrochloride),rimiterol, terbutaline (e.g. as sulphate), isoetharine, tulobuterol or4-hydroxy-7-[2-[[2-[[3-(2-phenylethoxy)propyl]sulfonyl]ethyl]amino]ethyl-2(3H)-benzothiazolone;adenosine 2a agonists, e.g.2R,3R,4S,5R)-2-[6-Amino-2-(1S-hydroxymethyl-2-phenyl-ethylamino)purin-9-yl]-5-(2-ethyl-2H-tetrazol-5-yl)-tetrahydro-furan-3,4-diol(e.g. as maleate); α₄ integrin inhibitors e.g.(2S)-3-[4-({[4-(aminocarbonyl)-1-piperidinyl]carbonyl}oxy)phenyl]-2-[((2S)-4-methyl-2-{[2-(2-methylphenoxy)acetyl]amino}pentanoyl)amino]propanoicacid (e.g. as free acid or potassium salt), diuretics, e.g., amiloride;anticholinergics, e.g., ipratropium (e.g. as bromide), tiotropium,atropine or oxitropium; hormones, e.g., cortisone, hydrocortisone orprednisolone; xanthines, e.g., aminophylline, choline theophyllinate,lysine theophyllinate or theophylline; therapeutic proteins andpeptides, e.g., insulin or glucagon; vaccines, diagnostics, and genetherapies. It will be clear to a person skilled in the art that, whereappropriate, the medicaments may be used in the form of salts, (e.g., asalkali metal or amine salts or as acid addition salts) or as esters(e.g., lower alkyl esters) or as solvates (e.g., hydrates) to optimisethe activity and/or stability of the medicament.

The medicament product may in aspects, be a mono-therapy (i.e. singleactive medicament containing) product or it may be a combination therapy(i.e. plural active medicaments containing) product.

Suitable medicaments or medicament components of a combination therapyproduct are typically selected from the group consisting ofanti-inflammatory agents (for example a corticosteroid or an NSAID),anticholinergic agents (for example, an M₁, M₂, M₁/M₂ or M₃ receptorantagonist), other β₂-adrenoreceptor agonists, antiinfective agents(e.g. an antibiotic or an antiviral), and antihistamines. All suitablecombinations are envisaged.

Suitable anti-inflammatory agents include corticosteroids and NSAIDs.Suitable corticosteroids which may be used in combination with thecompounds of the invention are those oral and inhaled corticosteroidsand their pro-drugs which have anti-inflammatory activity. Examplesinclude methyl prednisolone, prednisolone, dexamethasone, fluticasonepropionate,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difluoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioicacid S-(2-oxo-tetrahydro-furan-3S-yl) ester, beclomethasone esters (e.g.the 17-propionate ester or the 17,21-dipropionate ester), budesonide,flunisolide, mometasone esters (e.g. the furoate ester), triamcinoloneacetonide, rofleponide, ciclesonide, butixocort propionate, RPR-106541,and ST-126. Preferred corticosteroids include fluticasone propionate,6α,9α-difluoro-11β-hydroxy-16α-methyl-17α-[(4-methyl-1,3-thiazole-5-carbonyl)oxy]-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester and6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester, more preferably6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester.

Suitable NSAIDs include sodium cromoglycate, nedocromil sodium,phosphodiesterase (PDE) inhibitors (e.g. theophylline, PDE4 inhibitorsor mixed PDE3/PDE4 inhibitors), leukotriene antagonists, inhibitors ofleukotriene synthesis, iNOS inhibitors, tryptase and elastaseinhibitors, beta-2 integrin antagonists and adenosine receptor agonistsor antagonists (e.g. adenosine 2a agonists), cytokine antagonists (e.g.chemokine antagonists) or inhibitors of cytokine synthesis. Suitableother β₂-adrenoreceptor agonists include salmeterol (e.g. as thexinafoate), salbutamol (e.g. as the sulphate or the free base),formoterol (e.g. as the fumarate), fenoterol or terbutaline and saltsthereof.

Suitable phosphodiesterase 4 (PDE4) inhibitors include compounds thatare known to inhibit the PDE4 enzyme or which are discovered to act as aPDE4 inhibitor, and which are only PDE4 inhibitors, not compounds whichinhibit other members of the PDE family as well as PDE4. Generally it ispreferred to use a PDE4 inhibitor which has an IC₅₀ ratio of about 0.1or greater as regards the IC₅₀ for the PDE4 catalytic form which bindsrolipram with a high affinity divided by the IC₅₀ for the form whichbinds rolipram with a low affinity. For the purposes of this disclosure,the cAMP catalytic site which binds R and S rolipram with a low affinityis denominated the “low affinity” binding site (LPDE 4) and the otherform of this catalytic site which binds rolipram with a high affinity isdenominated the “high affinity” binding site (HPDE 4).

This term “HPDE4” should not be confused with the term “hPDE4” which isused to denote human PDE4.

A method for determining IC₅₀s ratios is set out in U.S. Pat. No.5,998,428 which is incorporated herein in full by reference as thoughset out herein. See also PCT application WO 00/51599 for an anotherdescription of said assay.

Suitable PDE4 inhibitors include those compounds which have a salutarytherapeutic ratio, i.e., compounds which preferentially inhibit cAMPcatalytic activity where the enzyme is in the form that binds rolipramwith a low affinity, thereby reducing the side effects which apparentlyare linked to inhibiting the form which binds rolipram with a highaffinity. Another way to state this is that the preferred compounds willhave an IC₅₀ ratio of about 0.1 or greater as regards the IC₅₀ for thePDE4 catalytic form which binds rolipram with a high affinity divided bythe IC₅₀ for the form which binds rolipram with a low affinity.

A further refinement of this standard is that of one wherein the PDE4inhibitor has an IC₅₀ ratio of about 0.1 or greater; said ratio is theratio of the IC₅₀ value for competing with the binding of 1 nM of[³H]R-rolipram to a form of PDE4 which binds rolipram with a highaffinity over the IC₅₀ value for inhibiting the PDE4 catalytic activityof a form which binds rolipram with a low affinity using 1 μM[³H]-cAMPas the substrate.

Most suitable are those PDE4 inhibitors which have an IC₅₀ ratio ofgreater than 0.5, and particularly those compounds having a ratio ofgreater than 1.0. Preferred compounds are cis4-cyano-4-(3-cyclopentyloxy-4-methoxyphenyl)cyclohexan-1-carboxylicacid,2-carbomethoxy-4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-oneandcis-[4-cyano-4-(3-cyclopropylmethoxy-4-difluoromethoxyphenyl)cyclohexan-1-ol];these are examples of compounds which bind preferentially to the lowaffinity binding site and which have an IC₅₀ ratio of 0.1 or greater.

Other suitable medicament compounds include:cis-4-cyano-4-[3-(cyclopentyloxy)-4-methoxyphenyl]cyclohexane-1-carboxylicacid (also known as cilomalast) disclosed in U.S. Pat. No. 5,552,438 andits salts, esters, pro-drugs or physical forms; AWD-12-281 from elbion(Hofgen, N. et al. 15th EFMC Int Symp Med Chem (September 6-10,Edinburgh) 1998, Abst P. 98; CAS reference No. 247584020-9); a9-benzyladenine derivative nominated NCS-613 (INSERM); D4418 fromChiroscience and Schering Plough; a benzodiazepine PDE4 inhibitoridentified as CI-1018 (PD-168787) and attributed to Pfizer; abenzodioxole derivative disclosed by Kyowa Hakko in WO99/16766; K-34from Kyowa Hakko; V-11294A from Napp (Landells, L. J. et al. Eur Resp J[Annu Cong Eur Resp Soc (September 19-23, Geneva) 1998] 1998, 12 (Suppl.28): Abst P2393); roflumilast (CAS reference No 162401-32-3) and apthalazinone (WO99/47505, the disclosure of which is hereby incorporatedby reference) from Byk-Gulden; Pumafentrine,(−)-p-[(4aR*,10bS*)-9-ethoxy-1,2,3,4,4a,10b-hexahydro-8-methoxy-2-methylbenzo[c][1,6]naphthyridin-6-yl]-N,N-diisopropylbenzamidewhich is a mixed PDE3/PDE4 inhibitor which has been prepared andpublished on by Byk-Gulden, now Altana; arofylline under development byAlmirall-Prodesfarma; VM554/UM565 from Vernalis; or T-440 (TanabeSeiyaku; Fuji, K. et al. J Pharmacol Exp Ther, 1998, 284(1): 162), andT2585.

Suitable anticholinergic agents are those compounds that act asantagonists at the muscarinic receptor, in particular those compounds,which are antagonists of the M₁ and M₂ receptors. Exemplary compoundsinclude the alkaloids of the belladonna plants as illustrated by thelikes of atropine, scopolamine, homatropine, hyoscyamine; thesecompounds are normally administered as a salt, being tertiary amines.

Particularly suitable anticholinergics include ipratropium (e.g. as thebromide), sold under the name Atrovent, oxitropium (e.g. as the bromide)and totropium (e.g. as the bromide) (CAS-139404-48-1). Also of interestare: methantheline (CAS-53-46-3), propantheline bromide (CAS-50-34-9),anisotropine methyl bromide or Valpin 50 (CAS-80-50-2), clidiniumbromide (Quarzan, CAS-3485-62-9), copyrrolate (Robinul), isopropamideiodide (CAS-71-81-8), mepenzolate bromide (U.S. Pat. No. 2,918,408),tridihexethyl chloride (Pathilone, CAS-4310-35-4), and hexocycliummethylsulfate (Tral, CAS-115-63-9). See also cyclopentolatehydrochloride (CAS-5870-29-1), tropicamide (CAS-1508-75-4),trihexyphenidyl hydrochloride (CAS-144-11-6), pirenzepine(CAS-29868-97-1), telenzepine (CAS-80880-90-9), AF-DX 116, ormethoctramine, and the compounds disclosed in WO01/04118.

Suitable antihistamines (also referred to as H₁-receptor antagonists)include any one or more of the numerous antagonists known which inhibitH₁-receptors, and are safe for human use. All are reversible,competitive inhibitors of the interaction of histamine withH₁-receptors. Examples include ethanolamines, ethylenediamines, andalkylamines. In addition, other first generation antihistamines includethose which can be characterized as based on piperizine andphenothiazines. Second generation antagonists, which are non-sedating,have a similar structure-activity relationship in that they retain thecore ethylene group (the alkylamines) or mimic the tertiary amine groupwith piperizine or piperidine. Exemplary antagonists are as follows:

-   Ethanolamines: carbinoxamine maleate, clemastine fumarate,    diphenylhydramine hydrochloride, and dimenhydrinate.-   Ethylenediamines: pyrilamine amleate, tripelennamine HCl, and    tripelennamine citrate.-   Alkylamines: chiropheniramine and its salts such as the maleate    salt, and acrivastine.-   Piperazines: hydroxyzine HCl, hydroxyzine pamoate, cyclizine HCl,    cyclizine lactate, meclizine HCl, and cetirizine HCl.-   Piperidines: Astemizole, levocabastine HCl, loratadine or its    descarboethoxy analogue, and terfenadine and fexofenadine    hydrochloride or another pharmaceutically acceptable salt.

Azelastine hydrochloride is yet another H₁ receptor antagonist which maybe used in combination with a PDE4 inhibitor.

Particularly suitable anti-histamines include methapyrilene andloratadine.

In respect of combination products, co-formulation compatibility isgenerally determined on an experimental basis by known methods and maydepend on chosen type of medicament dispenser action.

The medicament components of a combination product are suitably selectedfrom the group consisting of anti-inflammatory agents (for example acorticosteroid or an NSAID), anticholinergic agents (for example, an M₁,M₂, M₁/M₂ or M₃ receptor antagonist), other β₂-adrenoreceptor agonists,antiinfective agents (e.g. an antibiotic or an antiviral), andantihistamines. All suitable combinations are envisaged.

Suitably, the co-formulation compatible components comprise aβ₂-adrenoreceptor agonist and a corticosteroid; and the co-formulationincompatible component comprises a PDE-4 inhibitor, an anti-cholinergicor a mixture thereof. The β₂-adrenoreceptor agonists may for example besalbutamol (e.g., as the free base or the sulphate salt) or salmeterol(e.g., as the xinafoate salt) or formoterol (eg as the fumarate salt).The corticosteroid may for example, be a beclomethasone ester (e.g., thedipropionate) or a fluticasone ester (e.g., the propionate) orbudesonide.

In one example, the co-formulation compatible components comprisefluticasone propionate and salmeterol, or a salt thereof (particularlythe xinafoate salt) and the co-formulation incompatible componentcomprises a PDE-4 inhibitor, an anti-cholinergic (e.g. ipratropiumbromide or tiotropium bromide) or a mixture thereof.

In another example, the co-formulation compatible components comprisebudesonide and formoterol (e.g. as the fumarate salt) and theco-formulation incompatible component comprises a PDE-4 inhibitor, ananti-cholinergic (e.g. ipratropium bromide or tiotropium bromide) or amixture thereof.

Generally, powdered medicament particles suitable for delivery to thebronchial or alveolar region of the lung have an aerodynamic diameter ofless than 10 micrometers, preferably less than 6 micrometers. Othersized particles may be used if delivery to other portions of therespiratory tract is desired, such as the nasal cavity, mouth or throat.The medicament may be delivered as pure drug, but more appropriately, itis preferred that medicaments are delivered together with excipients(carriers) which are suitable for inhalation. Suitable excipientsinclude organic excipients such as polysaccharides (i.e. starch,cellulose and the like), lactose, glucose, mannitol, amino acids, andmaltodextrins, and inorganic excipients such as calcium carbonate orsodium chloride. Lactose is a preferred excipient.

Particles of powdered medicament and/or excipient may be produced byconventional techniques, for example by micronisation, milling orsieving. Additionally, medicament and/or excipient powders may beengineered with particular densities, size ranges, or characteristics.Particles may comprise active agents, surfactants, wall formingmaterials, or other components considered desirable by those of ordinaryskill.

The excipient may be included with the medicament via well-knownmethods, such as by admixing, co-precipitating and the like. Blends ofexcipients and drugs are typically formulated to allow the precisemetering and dispersion of the blend into doses. A standard blend, forexample, contains 13000 micrograms lactose mixed with 50 microgramsdrug, yielding an excipient to drug ratio of 260:1. Dosage blends withexcipient to drug ratios of from 100:1 to 1:1 may be used. At very lowratios of excipient to drug, however, the drug dose reproducibility maybecome more variable.

The medicament pack and dispenser device of the invention is in oneaspect suitable for dispensing medicament for the treatment ofrespiratory disorders such as disorders of the lungs and bronchialtracts including asthma and chronic obstructive pulmonary disorder(COPD). In another aspect, the invention is suitable for dispensingmedicament for the treatment of a condition requiring treatment by thesystemic circulation of medicament, for example migraine, diabetes, painrelief e.g. inhaled morphine.

Accordingly, there is provided the use of a medicament pack anddispenser device according to the invention for the treatment of arespiratory disorder, such as asthma and COPD. Alternatively, thepresent invention provides a method of treating a respiratory disordersuch as, for example, asthma and COPD, which comprises administration byinhalation of an effective amount of medicament product as hereindescribed from a medicament pack or dispenser device of the presentinvention.

The amount of any particular medicament compound or a pharmaceuticallyacceptable salt, solvate or physiologically functional derivativethereof which is required to achieve a therapeutic effect will, ofcourse, vary with the particular compound, the route of administration,the subject under treatment, and the particular disorder or diseasebeing treated. The medicaments for treatment of respiratory disordersherein may for example, be administered by inhalation at a dose of from0.0005 mg to 10 mg, preferably 0.005 mg to 0.5 mg. The dose range foradult humans is generally from 0.0005 mg to 100 mg per day andpreferably 0.01 mg to 1 mg per day.

It will be understood that the present disclosure is for the purpose ofillustration only and the invention extends to modifications, variationsand improvements thereto.

The application of which this description and claims form part may beused as a basis for priority in respect of any subsequent application.The claims of such subsequent application may be directed to any featureor combination of features described therein. They may take the form ofproduct, method or use claims and may include, by way of example andwithout limitation, one or more of the following claims.

1. A blister form medicament pack adapted for use in an inhalationdevice comprising (a) a base sheet in which blisters are formed todefine pockets therein, the pockets containing inhalable medicament indry powder form; (b) a lid sheet which is sealed to the base sheetexcept in the region of the blisters and mechanically peelable from thebase sheet to enable release of said inhalable medicament, wherein saidbase sheet has a laminate structure comprising (a) a first layer ofaluminium foil; and (b) a second layer of polymeric material ofthickness from 10 to 60 micron, said polymeric material having a watervapour permeability of less than 0.6 g /(100 inches²) (24 hours) (mil)at 25° C.
 2. A blister form medicament pack according to claim 1,wherein the polymeric material is selected from the group consisting ofpolypropylene; polyethylene; polyvinylidene chloride (PVDC);polychlorotrifluoroethylene (PCTFE); cyclic olefin copolymer (COC); andcyclic olefin polymer (COP).
 3. A blister form medicament pack accordingto claim 2, wherein the polymeric material is polypropylene having aform selected from the group consisting of oriented or cast form.
 4. Ablister form medicament pack according to claim 2, wherein the polymericmaterial is polyethylene having a form selected from the groupconsisting of high, low or intermediate density form.
 5. A blister formmedicament pack according to claim 1, in the form of an elongatepeelable blister strip having multiple distinct blister portionsprovided along its length.
 6. A blister form medicament pack accordingto claim 1, wherein the polymeric material of the second layer has awater vapour permeability of less than 0.3 g/(100 inches²) (24 hours)(mil) at 25° C.
 7. A blister form medicament pack according to claim 1,wherein the thickness of the second layer is from 20 to 30 micron.
 8. Ablister form medicament pack according to claim 1, wherein the secondlayer is an inner layer of the pack.
 9. A blister form medicament packaccording to any of claims 1 to 8, wherein the lid sheet comprises atleast the following successive layers: (a) paper; bonded to (b) plasticfilm; bonded to (c) aluminium foil.
 10. A blister form medicament packaccording to claim 9, wherein the aluminium foil is further providedwith a layer of heat seal lacquer.
 11. A blister form medicament packaccording to claim 9, wherein said plastic film layer comprises amaterial selected from the group consisting of polyester, polyamide,polypropylene and PVC.
 12. A blister form medicament pack according toclaim 11, wherein the plastic film is an oriented plastic filmcomprising a material selected from the group consisting of orientedpolyamide (OPA), oriented polyester (OPET), and oriented polypropylene(OPP).
 13. A blister form medicament pack according to claim 11, whereinthe plastic layer has a thickness of from 5 to 40 μm.
 14. A blister formmedicament pack according to claim 9, wherein the aluminium layer has athickness of from 15 to 60 μm.
 15. A blister form medicament packaccording to claim 1, wherein the base sheet comprises at least thefollowing successive layers: (a) oriented polyamide (OPA); adhesivelybonded to (b) aluminium foil; adhesively bonded to (c) a layer ofthickness from 10 to 60 micron comprising the polymeric material havinga water vapour permeability of less than 0.6 g/(100 inches²) (24 hours)(mil) at 25° C.
 16. A blister form medicament pack according to claim15, wherein the polymeric material comprises oriented polypropylene(OPP) and the thickness of the polymeric layer is from 20 to 30 micron.17. A blister form medicament pack according to claim 15, wherein thepolymeric material comprises cast polypropylene and the thickness of thepolymeric layer is from 20 to 30 micron.
 18. A blister form medicamentpack according to claim 15, wherein the polymeric material compriseshigh density polyethylene (HDPE) and the thickness of the polymericlayer is from 35 to 45 micron.
 19. A blister form medicament packaccording to claim 15, wherein the polymeric material comprises lowdensity polyethylene (LDPE) and the thickness of the polymeric layer isfrom 20 to 30 micron.
 20. A blister form medicament pack according toclaim 15, wherein the polymeric material comprises polyvinylidenechloride (PVDC) and the thickness of the polymeric layer is from 20 to30 micron.
 21. A blister form medicament pack according to claim 15,wherein the polymeric material comprises polychlorotrifluoroethylene(PCTFE) and the thickness of the polymeric layer is 20 to 45 micron. 22.A blister form medicament pack according to claim 15, wherein thepolymeric material comprises cyclic olefin copolymer (COC) and thethickness of the polymeric layer is from 20 to 30 micron.
 23. A blisterform medicament pack according to claim 1, wherein said inhalablemedicament comprises one or more medicament actives selected from thegroup consisting of anti-inflammatory agents, anticholinergic agents,other β₂-adrenoreceptor agonists, antiinfective agents, antihistaminesand any mixtures thereof.
 24. A blister form medicament pack accordingto claim 23, wherein said anti-inflammatory agents are selected from thegroup consisting of corticosteroids, NSAIDs and any mixtures thereof.25. A blister form medicament pack according to claim 24, wherein saidcorticosteroids are selected from the group consisting of methylprednisolone, prednisolone, dexamethasone, fluticasone propionate,6α,9α-difluoro-17α-[(2-furanylcarbonyl)oxy]-11β-hydroxy-16α-methyl-3-oxo-androsta-1,4-diene-17β-carbothioicacid S-fluoromethyl ester,6α,9α-difiuoro-11β-hydroxy-16α-methyl-3-oxo-17α-propionyloxy-androsta-1,4-diene-17β-carbothioic acid S-(2-oxo-tetrahydro-furan-3S-yl)ester, beclomethasone esters, flunisolide, mometasone esters,triamcinolone acetonide, rofleponide, ciclesonide, butixocortpropionate, RPR-106541, and ST-126 and any mixtures thereof.
 26. Ablister form medicament pack according to claim 24, wherein said NSAIDsare selected from the group consisting of sodium cromoglycate,nedocromil sodium, phosphodiesterase (PDE) inhibitors, leukotrieneantagonists, inhibitors of leukotriene synthesis, iNOS inhibitors,tryptase and elastase inhibitors, beta-2 integrin antagonists, adenosinereceptor agonists or antagonists, cytokine antagonists, inhibitors ofcytokine synthesis and any mixtures thereof.
 27. A blister formmedicament pack adapted for use in an inhalation device comprising: (a)a base sheet in which blisters are formed to define pockets therein forthe containment of inhalable medicament; (b) a lid sheet which is sealedto the base sheet except in the region of the blisters and mechanicallypeelable from the base sheet to enable release of said inhalablemedicament, wherein one or more of the blisters contain inhalablemedicament in dry powder form, and said base sheet has a laminatestructure comprising at least the following successive layers: (a)oriented polyamide (OPA); adhesively bonded to (b) aluminum foil;adhesively bonded to (c) an inner layer of polymeric material ofthickness from 10 to 60 micron, said polymeric material having a watervapour permeability of less than 0.6 g/(100 inches²) (24 hours) (mil) at25 C, said lid sheet has a laminate structure comprising at least thefollowing successive layers: (a) paper; bonded to (b) plastic film;bonded to (c) aluminum foil, and said aluminum foil layer of the lidsheet has a coating layer for bonding to the base sheet, the coatinglayer selected from the group consisting of heat seal lacquer, film andextrusion coating.
 28. A blister form medicament pack according to claim1, wherein the second layer is disposed inwardly of the first layer withrespect to the lid sheet.
 29. A blister form medicament pack accordingto claim 28, wherein the lid sheet and the base sheet are sealedtogether through a bonding material which bonds an inner face of the lidsheet to an inner face of the base sheet which is presented by thesecond layer.
 30. A blister form medicament pack according to claim 29,wherein the first and second layers of the base sheet are successivelayers of the base sheet which are bonded together.
 31. A blister formmedicament pack according to claim 30, wherein the polymeric material ofthe second layer is selected from the group consisting of apolypropylene and a polyethylene.
 32. A blister form medicament packaccording to claim 31, wherein the base sheet consists essentially ofthe first layer, the second layer and an outer layer of a polymericmaterial which is bonded to the first layer.
 33. A blister formmedicament pack according to claim 32, wherein the outer layer is of anoriented polyimide.